1. Field of the Invention
The present invention relates to diseases of iron metabolism, hepcidin and hemojuvelin.
2. Description of the Related Art
Various diseases of iron metabolism are known in the art and include hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, thalassemia, thalassemia intermedia, alpha thalassemia, sideroblastic anemia, porphyria, porphyria cutanea tarda, African iron overload, hyperferritinemia, ceruloplasmin deficiency, atransferrinemia, congenital dyserythropoietic anemia, anemia of chronic disease, anemia, hypochromic microcytic anemia, iron-deficiency anemia, conditions with hepcidin excess, Friedreich ataxia, gracile syndrome, Hallervorden-Spatz disease, Wilson's disease, pulmonary hemosiderosis, hepatocellular carcinoma, cancer, hepatitis, cirrhosis of liver, pica, chronic renal failure, insulin resistance, diabetes, atherosclerosis, neurodegenerative disorders, multiple sclerosis, Parkinson's Disease, Huntington's Disease, Alzheimer's Disease.
Juvenile hemochromatosis (JH) is an early-onset inherited disorder of iron overload. Two phenotypically very similar forms have been recently characterized, one due to the homozygous disruption of the HJV gene encoding a protein named hemojuvelin, and the other due to the homozygous disruption of the HAMP gene encoding hepcidin. See Papanikolaou, G, et al. (2004) Nat. Genet. 36:77-82. Hepcidin is a key iron-regulatory peptide hormone which controls extracellular iron concentration by regulating the major iron flows into plasma, and normally constrains intestinal iron absorption. See Ganz, T. (2005) Best Pract. Res. Clin. Haematol. 18:171-182. Although a few mutated forms of juvenile hemochromatosis gene (HFE2A) have been identified and may be suitable for detecting the mutations, no suitable therapeutic has been identified and shown to have a therapeutic effect. See Samuels, et al. WO 2004092405.
Anemia of chronic disease (alternatively known as anemia of inflammation) is another disease of iron metabolism due to the excessive production of the iron-regulatory hormone hepcidin. See Rivera, S., et al. (2005) Blood 105:1797-1802; Nemeth, E., et al. (2004) J. Clin. Invest 113:1271-1276; Roy & Andrews (2005) Curr. Opin. Hematol. 12:107-111; Fleming & Sly (2001) PNAS USA 98:8160-8162; and Weiss & Goodnough (2005) N. Engl. J. Med. 352:1011-1023. Anemia of chronic disease is a condition associated with inflammatory diseases including rheumatological disorders, inflammatory bowel diseases, chronic infections, chronic renal diseases, as well as with malignant disorders including various forms of cancer, lymphomas and multiple myeloma, and the like.
In anemia of chronic disease (anemia of inflammation) the production of hepcidin is stimulated by various cytokines including interleukin-6. Hepcidin acts by binding to ferroportin, the sole known cellular iron exporter, and inducing its degradation. Excess hepcidin causes the loss of ferroportin from the surfaces of macrophages engaged in the recycling of iron from senescent red cells. See Nemeth, E., et al. (2004) Science 306:2090-2093. As a result, iron is trapped in macrophages and blood iron concentrations decrease, restricting the flow of iron to the bone marrow, and thus slowing the production of hemoglobin and consequently decreasing the production of red blood cells. See Rivera, S., et al. (2005). Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs, Blood (2005). Unfortunately, suitable and effective therapies for anemia of chronic disease are limited. Specifically, the three main therapies are based on (1) treating the underlying disease which is usually not possible, otherwise this diagnosis would not exist, (2) erythropoietin administration which is effective in only about 50% of all the patients and is associated with undesirable side effects, and (3) transfusions which are undesirable due to contamination, infection and iron overload.
Thus, a need still exists for compositions and methods for treating diseases of iron metabolism, such as juvenile hemochromatosis and anemia of chronic disease.